肠上皮细胞STAT3调控Aldh1a1/RA轴促进肠-肝CD103+DC平衡在NASH中的机制研究

CD103+树突细胞（DC）可维持肠-肝免疫平衡，防止NASH进展，但其上游机制尚未明确。我们发现，在NASH小鼠IEC中，Aldh1a1/RA轴异常激活并介导肠-肝CD103+DC失衡。体内外实验证实，在IEC中STAT3可负调控Aldh1a1表达。特异性敲除NASH小鼠IEC中的STAT3，可加剧小鼠RA代谢紊乱和肠-肝CD103+DC失衡，加重NASH；而外源性补充RA则可恢复RA代谢平衡，并抵消敲除STAT3对NASH的加重作用。据此，我们提出假说：肠上皮细胞STAT3通过抑制Aldh1a1启动子，降低肠道RA异常分泌，维持肠-肝CD103+DC平衡，进而抑制NASH进展。本项目拟利用CD103+DC输注、启动子截短突变、ChIP等方法，探讨STAT3调控Aldh1a1/RA轴促进肠-肝CD103+DC平衡的机制。研究结果将帮助我们更好地理解“肠-肝轴”并为治疗NASH提供新思路。

CD103+ dendritic cell (DC) could maintain gut-liver immune balance, thus preventing non-alcoholic steatohepatitis (NASH) progression. However, the upstream mechanism that regulates CD103+DC remains unclear. Previously, we discovered that the over-activated Aldh1a1/retinoic acid (RA) axis in intestinal epithelial cell (IEC) contributed to gut-liver imbalance of CD103+DC in NASH mice. In vivo and in vitro study indicated that Aldh1a1 was negatively regulated by signal transducers and activators of transcription 3 (STAT3) in IEC. Conditional knockout of STAT3 in IEC aggravated metabolic disturbance of RA and subsequent gut-liver imbalance of CD103+DC, promoting NASH progression. Supplementation of RA could restore RA balance and then offset the aggravating effect of conditional knockout of STAT3 on NASH. Based on our study, we hypothesize that STAT3 in IEC suppresses NASH progression by targeting Aldh1a1 promoter, preventing over-production of RA in IEC and thereby maintaining the gut-liver balance of CD103+DC. In this project, we aim to investigate the detailed mechanism through which STAT3 in IEC regulates Aldh1a1/RA axis and maintain gut-liver balance of CD103+DC, by using methods including transfer of CD103+DC to NASH mice, Aldh1a1 promoter truncation and mutation, chromatin immunoprecipitation(ChIP),etc. Hopefully, our findings would help with better understanding of “gut-liver axis” and shed new light on treatment for NASH.